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First published online 4 October 2006
doi: 10.1242/dev.02612
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1 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute,
Cambridge CB2 4AT, UK.
2 Howard Hughes Medical Institute, Department of Molecular Biology,
Massachusetts General Hospital, Department of Genetics, Harvard Medical School
Boston, MA 02114, USA.
Author for correspondence (e-mail:
wolf.reik{at}bbsrc.ac.uk)
Accepted 5 September 2006
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SUMMARY |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Key words: Epigenetics, Imprinting, ES and TS cells, Kcnq1 domain, Mouse
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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;
Lewis et al., 2004;
Li et al., 1993;
Reik and Walter, 2001;
Umlauf et al., 2004). Most
imprinted genes occur in clusters in the mammalian genome. Within a cluster,
the imprinting of multiple genes is often regulated in a coordinated fashion,
involving imprinting centres that acquire allele-specific DNA methylation in
the parental germ cells. To date, there are two principal mechanisms described
by which an allele-specific DNA methylation mark can lead to imprinting of a
cluster of genes (Lewis and Reik,
2006). The first involves inactivating a chromatin insulator by
DNA methylation; distal enhancers are prevented from accessing promoters on
the unmethylated allele by a repressive higher order chromatin structure but
can activate transcription on the methylated allele. This mechanism regulates
the Igf2-H19 imprinting cluster
(Bell and Felsenfeld, 2000;
Hark et al., 2000;
Kanduri et al., 2000;
Murrell et al., 2004). The
second involves a DNA methylation mark that represses a non-coding RNA
transcript on one parental allele. On the other allele the non-coding
transcript is expressed leading to the repression of flanking genes by
targeting polycomb proteins and repressive histone modifications to the
region. This mechanism regulates imprinted X inactivation in mouse placenta
and is also likely to occur in the Igf2r and Kcnq1 domains
(Heard, 2004;
Huynh and Lee, 2003;
Lewis et al., 2004;
Sleutels et al., 2002;
Umlauf et al., 2004).
The Kcnq1 imprinted domain lies on distal mouse chromosome 7 and
contains one paternally expressed gene, the non-coding RNA Kcnq1ot1,
several flanking genes which are paternally repressed in all lineages (we term
these ubiquitously imprinted genes) and other flanking genes which are
paternally repressed in placental lineages but are not imprinted in embryonic
lineages (Engemann et al.,
2000; Paulsen et al.,
2000). It contains two differentially methylated regions (DMRs):
one is a germline imprint which acts as the imprinting centre (IC2) and
contains the promoter of the non-coding Kcnq1ot1 gene; the other is a
secondary imprint upstream of the cell cycle regulator Cdkn1c which
is not established until postimplantation stages of development
(Bhogal et al., 2004;
Engemann et al., 2000;
Fitzpatrick et al., 2002). The
other genes in the cluster have no associated differential DNA methylation
(Lewis et al., 2004).
Allele-specific histone modifications are also present at the locus. In the
embryo they are restricted to the DMRs. In extraembryonic lineages, however,
repressive histone modifications mark the entire cluster on the paternal
chromosome (with the exception of the Kcnq1ot1 region), while the
maternal chromosome is marked by histone modifications known to be associated
with active chromatin (Umlauf et al.,
2004). The repressive histone methylation marks on the paternal
chromosome depend on the presence of the Kcnq1ot1 gene
(Lewis et al., 2004), and gene
silencing in cis of both ubiquitously and placentally imprinted genes indeed
requires the Kcnq1ot1 transcript, or transcriptional elongation at
the Kcnq1ot1 promoter
(Mancini-Dinardo et al.,
2006).
There are several mechanistic similarities between imprinting in the
Kcnq1 domain and imprinted X chromosome inactivation
(Huynh and Lee, 2003;
Okamoto et al., 2004). The
non-coding RNA Xist is paternally expressed in the preimplantation
embryo and accompanied by exclusion of RNA polymerase II. Inactivation of
genes in cis is detected very early and is followed by acquisition of specific
repressive histone marks. By the morula-blastocyst stage, the majority of X
linked genes have been paternally silenced. This silencing becomes
pan-chromosomal and complete in extraembryonic tissues after implantation.
However, in the embryonic lineages, imprinted X inactivation must be
reprogrammed. Hence, in the inner cell mass (ICM) of female blastocysts,
silencing of the paternal genes on the X is erased and X-linked genes are
expressed biallelically in the epiblast and in ES cells, before random X
inactivation commences during early differentiation of epiblast cells
(Rastan, 1982;
Takagi et al., 1982).
By analogy with X inactivation, it has been proposed that genes in the
Kcnq1 domain become paternally silenced in the preimplantation
embryo, and placentally imprinted genes are reprogrammed in the ICM to be
biallelically expressed in the embryo, but continue to be imprinted in the
extra-embryonic tissues (Umlauf et al.,
2004). Testing of this model, and detailed mechanistic comparisons
with X inactivation, requires the study of the epigenetic dynamics of the
Kcnq1 domain in the preimplantation embryo.
Here, we investigate the establishment of imprinting in the Kcnq1 domain during preimplantation development and in embryonic stem (ES) and trophoblast stem (TS) cells as a model for the blastocyst stage of development. We show that Kcnq1ot1 is paternally expressed at the two-cell stage and retains its imprinting throughout preimplantation development. The ubiquitously imprinted genes also show monoallelic expression by the blastocyst stage. Unexpectedly, the placentally imprinted genes are still biallelically expressed in blastocysts. ES and TS cells precisely mirror this pattern of expression and we thus used them as a model system to study allele specific histone modifications. The ubiquitously imprinted genes indeed exhibit differential histone modifications while placentally imprinted genes are not differentially marked. Their silencing and differential histone marking arises during differentiation of the extraembryonic lineages between E4.5 and E7.5.
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MATERIALS AND METHODS |
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SUMMARY
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MATERIALS AND METHODS
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DISCUSSION
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). They were cultured on a layer of feeder mouse embryonic
fibroblasts (MEFs) in Dulbecco's modified Eagle medium containing 15% foetal
bovine serum and 103 U of leukaemia inhibitory factor per ml.
Before ES cells were used for RNA or ChIP analysis MEFs were removed by
panning. C57BL/6JxM.m. castaneus TS cells
(Huynh and Lee, 2003) were
cultured on a layer of feeder MEFs in RPMI 1640 medium containing 20% fetal
bovine serum, 25 ng/ml basic fibroblast growth factor and 1 µg/ml heparin.
Before TS cells were used for RNA or ChIP analysis, they were taken through
one passage without feeder cells to ensure minimal contamination with
MEFs.
RNA analysis
Total RNA was isolated from cells, tissues and staged embryos at E9.5 using
the RNeasy mini kit (Qiagen) according to the manufacturer's instructions. The
RNA was treated with DnaseI (Roche) and purified by ethanol precipitation. RNA
(0.5-1 µg) was reverse transcribed with Superscript II (Invitrogen) or
Powerscript single shot (BD Biosciences), according to the manufacturer's
instructions. Analogous reactions were performed without reverse transcriptase
(RT) to control for DNA contamination. Amplification of cDNA was performed
using PCR primers from Table 1.
RNA was extracted from preimplantation embryos using Trizol (Sigma) and
treated with TURBO DNase (Ambion) according to the manufacturers instructions.
RNA (10-20 ng) was reverse transcribed and amplified in a one-step reaction
with Superscript III (Invitrogen) using primers from
Table 1.
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).
Briefly 
5x107 cells were collected and washed in PBS.
Nuclei were purified through a sucrose cushion and incubated with MNase to
obtain fragments of one to five nucleosomes in length. Approximately 20 µg
of chromatin was incubated with 5-10 µg of antibody overnight at 4°C.
We used the following antibodies: H3AcK9 and K14, H3K4me2 and H3K27me3 from
Upstate Biotechnology; and H3K9me2 from Abcam. The antibody chromatin
complexes were captured with ProteinA sepharose beads. After washing and
elution DNA was extracted from the input chromatin, bound and unbound
fractions. We analyzed DNA from the ChIP assays by PCR-SSCP using primers
listed in Table 2.
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).
Drosophila SL2 cells (5x107) were added to one mouse
E7.5 ectoplacental cone (EPC) and homogenised. Chromatin was then prepared and
the entire sample was used in a precipitation with the H3K4me2 antibodies as
above as well as a no-antibody control. The antibody complex was captured with
Immunopure immobilized protein A and Handee Spin Cup columns (Pierce). The
columns were then washed using the NaCl buffers previously described
(Fournier et al., 2002) and
eluted. PCR was carried out using primers from
Table 2. Using this approach we
maximised the amount of material to use in SSCP-PCR analysis.
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RESULTS |
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SUMMARY
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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;
Umlauf et al., 2004). We
wished to determine when during preimplantation development Kcnq1ot1
expression and imprinting arose, and when ubiquitously and placentally
imprinted genes were silenced (Fig.
1). Screening of EST library data indicated expression of
Kcnq1ot1 in two-cell embryos. In
Fig. 1B we show that the
non-coding RNA Kcnq1ot1 is paternally expressed as early as two-cell
embryos. This imprinted expression is maintained throughout preimplantation
development to the blastocyst stage (Fig.
1C; data not shown). The ubiquitously imprinted gene
Kcnq1 is paternally repressed at the morula/blastocyst stage
(Fig. 1C) confirming previous
results. Cdkn1c is also imprinted at this stage
(Umlauf et al., 2004). By
contrast, the placentally imprinted genes Tssc4 and Cd81
show biallelic expression in the blastocyst
(Fig. 1C), while Ascl2
expression is not detected until E5.5
(Tanaka et al., 1999;
Umlauf et al., 2004). These
results show clearly that the noncoding RNA is paternally expressed from the
two-cell stage, and that ubiquitously imprinted genes are paternally silenced
by the blastocyst stage, whereas the placentally imprinted genes continue to
be biallelically expressed.
ES and TS cell lines reflect imprinted expression in the blastocyst
We next wished to determine whether ES and TS cells faithfully reflect the
imprinting pattern we see in the blastocyst. In the same way that ES cells
have similar properties to the ICM, TS cells reflect properties of the TE
lineage from which they are derived and are able to contribute towards all
trophoblast cell types in conceptuses when reintroduced into blastocysts
(Bradley et al., 1984;
Bradley and Robertson, 1986;
Tanaka et al., 1998). We used
ES and TS cells from C57Bl6/JxM.m. castaneus F1 hybrids to
study allele-specific expression. First we determined absolute levels of
expression of each gene in the cluster by Q-PCR in ES and TS cells, their
differentiated derivatives (embryoid bodies and trophoblast giant cells,
respectively), and in E10.5 embryos and placentae (see Fig. S1 in the
supplementary material). Ascl2 and Kcnq1 showed only basal
levels of expression in ES and TS cell lines (see Fig. S1 in the supplementary
material) making it impossible to reliably assay allelic expression of these
two genes. For the remaining genes, we determined that the amplification of
each parental allele during RTPCR was in the linear range.
Similar to our results in blastocysts, we find that the non-coding RNA, Kcnq1ot1 is largely repressed on the maternal allele in ES and fully repressed in TS cells (Fig. 2). The ubiquitously imprinted genes Phlda2 and Cdkn1c show monoallelic maternal expression. The placentally imprinted genes Osbpl5 and Tssc4 show biallelic expression in the ES and TS cells, confirming that they accurately reflect the imprinting status of the blastocyst. Cd81 shows expression from both alleles in ES and TS cells, although there is some skewing towards the maternal allele in TS cells. We have controlled for primer bias and the final maternal to paternal ratio of Cd81 is 1:1 in ES cells and has a bias of 3.5: 1 in TS cells. Although this is not the same level of bias seen at later stages, it is possible that imprinting at each gene in the domain is established at slightly different times, with Cd81 imprinting occurring earlier than other placental specific genes.
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) in ES
cells. This is possibly due to the different genotype of the cell lines used
(C57Bl/6xM.m. castaneus versus C57Bl/6xMus
spretus) or to different K27me3 antibodies. The ubiquitously imprinted
genes Phlda2 and Cdkn1c are enriched for acetylation and
H3K4me2 on the maternal chromosome, and for H3K27me3 on the paternal
chromosome both in TS and ES cells. Previous observations show that in E9.5
placenta, H3K9me2 is also present on the paternal allele
(Lewis et al., 2004;
Umlauf et al., 2004), which
suggests that the chromatin-based repression continues to be established
during placental development. This is similar to imprinted X chromosome
inactivation, where K27me3 along the X chromosome is observed in
preimplantation embryos before K9me2
(Huynh and Lee, 2003;
Okamoto et al., 2004). We note
that in our ES and TS cells, K9me2 is associated only with regions that also
exhibit differential DNA methylation, as is commonly observed in regions of
heterochromatin and in vitro assays (Fuks
et al., 2003; Lehnertz et al.,
2003). In the placentally imprinted genes, no major differences in histone modifications are observed between the parental alleles in either ES or TS cells, with the exception of Cd81, which shows a paternal bias for K27me3 in TS cells, reflecting the skewed expression seen in this cell type. These results in stem cells, which are representative of the ICM and TE lineages, suggest that gene silencing and histone marks of ubiquitously imprinted genes are established during preimplantation development.
Placentally imprinted genes are silenced and epigenetically marked during differentiation of extra-embryonic lineages
The finding that placentally imprinted genes are biallelically expressed in
blastocysts and TS cells and lack allelic histone marks suggests that gene
silencing arises during differentiation of the trophectoderm lineage. We thus
investigated allelic expression and histone marks during differentiation in
vitro and in vivo. Upon differentiation of TS cells to trophoblast giant cells
there is no change in allele-specific expression or in histone modifications
along the locus (see Fig. S2 in the supplementary material). This may be due
to cell culture effects or a specific property of isolated trophoblast giant
cells (this has never been studied).
By contrast, allelic silencing and histone modification is observed in
vivo. Fig. 3B shows that at
E7.5 in the ectoplacental cone (EPC, a derivative of the trophectoderm), the
paternal allele of Tssc4 has been silenced. Similarly, Ascl2
and Cd81 also show imprinted expression by this stage
(Tanaka et al., 1999) (data
not shown). The maternal allele of Tssc4 is enriched for the active
modification H3K4me2, revealing that allelic silencing and histone
modifications are established between E4.5 and E7.5. The small numbers of
cells in the EPC at this stage (10,000) did not allow a more
comprehensive ChIP analysis.
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DISCUSSION |
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SUMMARY
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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;
Mancini-Dinardo et al., 2006).
Truncation of the transcript to just a few kilobases demonstrates that either
transcription or the full length RNA itself is necessary to silence the
paternal chromosome in cis. Other imprinting clusters show similar
characteristics. Air is a 108 kb noncoding RNA transcribed in an
antisense direction to Igf2r on chromosome 17
(Lyle et al., 2000).
Air is inactivated on the maternal allele by oocyte-derived
methylation and is essential for silencing of genes at the
Igf2r/Air locus (Wutz et
al., 1997; Zwart et al.,
2001). Truncation of the Air transcript to 3 kb also
results in loss of imprinting at the locus
(Sleutels et al., 2002) and
therefore, Air RNA or its transcription is a key element of the
imprinting control at the Igf2r/Air cluster. We have previously
proposed that the Kcnq1ot1 RNA silences by coating of the chromosome
followed by RNA polymerase II exclusion and by recruitment of repressive
histone modifications using a mechanism similar to that described for
X-chromosome inactivation (Lewis et al.,
2004; Umlauf et al.,
2004). Consistent with this proposal, Kcnq1ot1 RNA is
expressed from the two-cell stage, in parallel with Xist. Our
observation that ubiquitously imprinted genes are paternally silenced by the
blastocyst stage, and have acquired differential histone marks in ICM- and
TE-derived pluripotent cell lines, adds further weight to the suggestion that
the epigenetic dynamics of the Kcnq1 cluster and of imprinted X
inactivation share a number of significant features.
Our initial expectation for the placentally imprinted genes was therefore
that they would be monoallelically expressed in the TE and in TS cells. This
expectation was compatible with the model by Umlauf et al.
(Umlauf et al., 2004), who
proposed that this group of genes were paternally silenced during
preimplantation development, and reprogrammed to biallelic expression in the
epiblast, in further analogy with X-linked genes. Our results show clearly
that this is not the case, and that silencing and histone modifications of
these genes arise during early differentiation of the extra-embryonic
lineages. The Igf2r/Air cluster is comparable in size to the
Kcnq1 imprinted region cluster and encodes a mixture of ubiquitous
and tissue specific maternally expressed genes and biallelically expressed
genes along the locus (Zwart et al.,
2001; Lyle et al.,
2000). In this cluster imprinted expression of surrounding genes
is also established after initiation of expression of the non-coding RNA,
Air, although this occurs at a later stage of development than
Kcnq1ot1 (Lerchner and Barlow,
1997; Szabo and Mann,
1995).
How can ubiquitously imprinted genes in the Kcnq1 region be
silenced early on, yet placentally imprinted ones are silenced late and only
in the trophoblast lineage? Mancini-DiNardo et al.
(Mancini-DiNardo et al., 2006)
showed that the Kcnq1ot1 RNA is required to silence both groups of
genes, and they also acquire the same repressive histone modifications, albeit
with different kinetics. Because ubiquitously imprinted genes are located
closer to the Kcnq1ot1 transcription unit than placentally imprinted
ones (Fig. 1A), we suggest that
the RNA represses (in cis) the nearest genes initially and then spreads to
more-distant, placental-specific, genes in the trophoblast after implantation.
Repetitive elements in the region and/or higher-order chromatin structures
that differ between the embryo and placenta may influence putative RNA coating
and gene repression in cis. The different epigenetic response of embryo and
extra-embryonic tissues may also involve lineage-specific transcription
factors or epigenetic marks. The PRC2 proteins Eed and Ezh2 are located at
specific foci with Xist RNA in late blastocysts in the TE, where
imprinted X inactivation has occurred (Mak
et al., 2004). In the ICM where there is random X inactivation,
Eed and Ezh2 are present but a homogeneous staining is observed in the
nucleus. The PRC2 complex might be a good candidate for establishing
lineage-specific imprinting; indeed, imprinting of some genes in the
Kcnq1 cluster is partially lost in extra-embryonic tissues in the
Eed mutant (Mager et al.,
2003). However Eed, Ezh2 and Suz12 are associated with the
repressed paternal allele at many regions along the locus in ES cells
(Umlauf et al., 2004). Given
the similarity in expression and allele specific histone modifications between
TS and ES cells, we would expect that distribution of these PRC2 proteins
would be similar in TS cells and in the blastocyst. Therefore any lineage
specific differences would occur after implantation.
Although the distance between the Kcnq1ot1 transcription unit and
the placentally imprinted genes may partly explain the relatively slow
kinetics of their inactivation, these genes are still relatively close to
Kcnq1ot1 when compared with the distance between Xist and
distal genes on the X chromosome. There are several possible explanations for
the difference in timing between Xist and Kcnq1ot1 mediated
silencing. Kcnq1ot1 may be expressed at a lower level than
Xist during preimplantation development causing a slower accumulation
of RNA and a delay in coating. Alternatively, sequence features that promote
spreading of Xist and of repressive chromatin may occur at a higher
frequency on the X chromosome. It is known that Line 1 elements are enriched
twofold on the X chromosome compared with autosomes
(Bailey et al., 2000), and
there may be other features that affect the time required to establish
silencing. The Kcnq1ot1 transcript is longer than the Xist
transcript and, unlike Xist, there are no known introns (L.R. et al.,
unpublished). These differences must affect the secondary structure and
possibly the stability of the RNAs.
Data shown here and in other recent publications demonstrate that
X-inactivation and autosomal imprinting do indeed have mechanistic
similarities. This strengthens the hypothesis that these two processes may
have evolved together (Lee,
2003; Reik and Lewis,
2005).
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/133/21/4203/DC1
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ACKNOWLEDGMENTS |
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Footnotes |
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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